Depot compositions for vesicular monoamine transporter 2 (vmat2) inhbitors

Abstract

The present invention provides a depot composition suitable to deliver a VMAT2 inhibitor in a controlled manner. The composition of the present invention comprises: (a) a VMAT2 inhibitor and (b) a pharmaceutically acceptable oil. Optionally, the depot composition of the present invention also comprises an excipient to achieve optimal delivery of the VMAT2 inhibitor. The present invention also provides a method for making such depot composition.

What is claimed: 
     
         1 . A depot composition comprising: a) a vesicular monoamine transporter 2 (VMAT2) inhibitor or a pharmaceutically acceptable salt thereof; b) a pharmaceutically acceptable oil; and c) a lipid, wherein the lipid is a solid at a temperature between about 15 and about 30° C., and the lipid is present in an amount from 0% to about 50% by weight, relative to the weight of the depot composition. 
     
     
         2 . The depot composition of  claim 1 , wherein the VMAT2 inhibitor is selected from a group consisting of VBZ, (±)-TBZ, (+)-TBZ, (−)-TBZ, (±)-d6-TBZ, (+)-d6-TBZ and (−)-d6-TBZ. 
     
     
         3 . The depot composition of  claim 1 , wherein the VMAT2 inhibitor is selected from a group consisting of (+)-(α)-DHTBZ, (−)-(α)-DHTBZ, (+)-(β)-DHTBZ, (−)-(β)-DHTBZ, (+)-d6-(α)-DHTBZ, (−)-d6-(α)-DHTBZ, (+)-d6-(β)-DHTBZ, and (−)-d6-(β)-DHTBZ. 
     
     
         4 . The depot composition of  claim 1 , wherein the VMAT2 inhibitor is (+)-TBZ. 
     
     
         5 . The depot composition of  claim 1 , wherein the pharmaceutically acceptable oil is selected from the group consisting of triglycerides, vegetable oils, sesame oil, soybean oil, cottonseed oil, castor oil, olive oil, medium chain triglyceride (MCT), dioleate glycerol, ethyl oleate and ethyl linoleate. 
     
     
         6 . The depot composition of  claim 1 , wherein the lipid is selected from the group consisting of sterols, natural waxes, synthetic waxes, hydroxysteroid, and ketosteroid. 
     
     
         7 . The depot composition of  claim 1 , wherein the lipid is cholesterol. 
     
     
         8 . The depot composition of  claim 1 , wherein the VMAT2 inhibitor or the pharmaceutically acceptable salt thereof is present in an amount of less than about 70% by weight, relative to the weight of the depot composition. 
     
     
         9 . The depot composition of  claim 1 , wherein the ratio of the lipid to the pharmaceutically acceptable oil is between about 1:1 and about 1:99 by weight. 
     
     
         10 . The depot composition of  claim 1 , wherein the lipid has a particle size distribution characterized by D(50) in a range from about 1 μm to about 100 μm. 
     
     
         11 . The depot composition of  claim 1 , wherein the VMAT2 inhibitor or the pharmaceutically acceptable salt thereof has a particle size distribution characterized by D(50) in a range from about 3 μm to about 300 μm. 
     
     
         12 . The depot composition of  claim 1 , wherein the VAMT2 inhibitor or the pharmaceutically acceptable salt thereof is dispersed in the depot composition that is filled in a syringe for subcutaneous or intramuscular injection. 
     
     
         13 . A method of treating a hyperkinetic movement disorder comprising administering to a patient in need thereof the depot composition of  claim 1  via injection. 
     
     
         14 . The method of  claim 13 , wherein an in situ sustained release depot is formed upon the administering to the patient, and the VMAT2 inhibitor or the pharmaceutically acceptable salt thereof is released to the patient for at least one week. 
     
     
         15 . The method of  claim 14 , which, after the administering, provides the release of the VMAT2 inhibitor or the pharmaceutically acceptable salt thereof with a plasma level peak/trough (P/T) ratio between about 1 to about 20. 
     
     
         16 . The method of  claim 14 , wherein the release of the VMAT2 inhibitor or the pharmaceutically acceptable salt thereof from the in situ sustained release depot is no more than about 30% of total amount of the VMAT2 inhibitor or the pharmaceutically acceptable salt thereof within 24 hours after the administration. 
     
     
         17 . The method of  claim 13 , wherein the hyperkinetic movement disorder is selected from the group consisting of tardive dyskinesia (TD), chorea associated with Huntington's disease (HD), tremors, dystonia, tics, myoclonus, stereotypies, restless legs syndrome, and various other disorders with abnormal involuntary movements. 
     
     
         18 . The depot composition of  claim 1 , wherein the depot composition has a viscosity between about 300,000 and about 10,000,000 mPas at room temperature when measured at a shear <0.1 s −1  and the viscosity is between about 1,000 and about 50,000 mPas at room temperature when measured at a shear >10 s −1 .